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21st Century
“Fits”Alexandre J. Lockfeld, M.D.
Clinical Neuroscience Practice 2010
18 May, 2010 Eugene, Oregon
Current Disclosures:
Alexandre J. Lockfeld, M.D.Adult Neurology and Epilepsy
Speaker‟s Bureau/Consultant: UCB, Inc.[ Keppra ® (levetiracetam); Vimpat ® (lacosamide) ]
Overview
• History of Epilepsy
• Seizure and Epilepsy Classification
• Epilepsy Statistics and Risks
• Issues for Women with Epilepsy
• Diagnosis of Epilepsy
• Status Epilepticus
• Pharmacologic Treatment of Epilepsy
• Surgical Treatment of Epilepsy
A Brief History of Epilepsy
• c. 2000 BC – First written description of epilepsy on clay tablets in Babylon. Cause believed to be demons or spirits
• c.400 BC – “On the Sacred Disease” written, attributed to Hippocrates. Cause believed to be blocked air flow in veins
• 177 AD – Galen delivers lecture “On the Brain” in Rome. Maintains that seizures are caused by pathologic humors or toxins
History of Epilepsy –
Hippocrates (b. 460 B.C.)On the Sacred Disease
“It is thus with regard to the disease called Sacred: it appears to me to be nowise more divine nor more sacred than other diseases, but has a natural cause from which it originates like other afflictions.
Men regard its nature and cause as divine from ignorance and wonder, because it is not at all like to other diseases.”
History of EpilepsyTreatment of Epilepsy in the Middle Ages:
• Even when well intentioned, treatment was
medieval
• Included early attempts at epilepsy surgery
History of Epilepsy
The Scientific Era
• 1849 – Robert Bentley Todd develops electrical theory of epilepsy
• Bromide introduced as first true antiepileptic
• 1870 – John Hughlings Jackson describes seizure origin in cerebral cortex
• 1886 - Sir Victor Horsley publishes series of 3 cases of successful (lucky!) brain surgery to relieve epilepsy
History of Epilepsy
20th Century Advances in Epilepsy
• 1912 – Phenobarbital (PB) introduced
• 1929 – Hans Berger develops EEG
• 1938 – Phenytoin (PHT) introduced
• 1950s – Temporal lobe resections for epilepsy
• 1970s – CT scanning becomes available
• 1974 – Carbamazepine (CBZ) approved
• 1978 – Valproic Acid (VPA) licensed in U.S.
• 1980s - MRI scanning becomes available
History of Epilepsy
At the Threshold of the New Millenium:
• 1993 – Felbamate (FBM) approved in US
• 1993 – Gabapentin (GPN) approved
• 1994 – Lamotrigine (LTG) approved
• 1996 – Topiramate (TPM) approved
• 1997 – Vagus nerve stimulation approved
• 1997 – Tiagabine (TGB) approved
• 1999 – Levetiracetam (LEV) approved
• 2000 – Oxcarbazepine (OXC) approved
• 2000 – Zonisamide (ZNS) approved
History of Epilepsy
The 21st Century Begins:
• 2005 - Pregabalin (PGB) approved in US
• 2008 - Rufinamide (RFN) approved
• 2009 - Lacosamide (LCS) approved
• 2009 – Vigabatrin (VGB) approved
• 2009 - NeuroPace ® Trial published
• 2010 - Sante DBS Trial published
Seizure and Epilepsy
Classification• International League Against Epilepsy
(ILAE) classification scheme
• Latest update 2009
• Older terminology e.g. “Grand Mal” is
proving impossible to eradicate…..
Seizure Classification:
ILAE SchemePartial Seizures Generalized Seizures
Focal/local onset bilateral onset
International classification of
seizures: Partial Onset
• Simple partial seizures: conciousness
not impaired
• Complex partial seizures: with
impairment of consciousness
• Partial seizures (simple or complex)
evolving to secondarily generalized
seizures
Seizure Classification:
Complex Partial Seizures• Altered
consciousness/awareness
• Duration one half to three minutes
• May occur in clusters
• Semiology varies with site of origin
• EEG: Interictal- sharp waves or spikes; Ictal-focal or bilateral rhythmic sharp
• Amnesia
• Purposeless automatisms
• Especially when of mesial temporal lobe origin, often difficult to control
Seizure Classification:
Secondarily Generalized Seizures
• Generalized tonic
clonic seizure may be
preceded by aura or
automatisms
• Distinguishing from
primary generalized
seizures may help
guide therapy
International classification of
seizures: Generalized Seizures
• Nonconvulsive (absence) Typical (3/sec
spike and slow wave complexes on EEG)
• Atypical (<3/sec spike and slow wave
complexes on EEG)
• Convulsive Myoclonic seizures
• Clonic seizures
• Tonic seizures
• Tonic-clonic seizures
• Atonic ("drop attacks")
Seizure Classification: Generalized
Tonic-Clonic Seizure
Seizure vs. EpilepsySEIZURE:
A sudden, excessive,
rapid and local
discharge of gray matter
J. Hughlings Jackson
EPILEPSY:
Recurrent unprovoked
seizures
Epilepsy Classification
SEIZURES vs. the EPILEPSIES:
• A SEIZURE is a sign or symptom of
cerebral paroxysmal discharge.
• The EPILEPSIES are syndromes or
diseases characterized by a tendency to
have recurrent seizures along with other
clinical characteristics.
Epilepsy Classification:
MYOCLONIC EPILEPSY
• Onset childhood to young adulthood
• Sudden jerks, usually bilateral, arms>legs
• One second in duration, often multiple
• May be photic or sensory triggered
• Often maximal on awakening
• EEG: generalized polyspike-wave burst
JUVENILE MYOCLONIC EPILEPSY
• Most common myoclonic epilepsy, genes identified
• Clinical triad of
– absence seizures (in one third)
– AM myoclonic jerks (characteristic)
– tonic-clonic seizures (in majority)
• Age of onset 8 to 26 years, peak at 12-18, persists life long
• Normal neurological state and development
• EEG shows generalized polyspike/wave bursts
• AEDs: valproic acid, lamotrigine, topiramate
ABSENCE EPILEPSY
• Childhood or teenage onset
• Sudden onset, without aura, prompt offset
• Momentary loss of consciousness, eyelid flutter
• 3-15 seconds duration
• Positive Family History
• EEG – 3 Hz spike/wave
• AEDs: ethosuximide, valproic acid, lamotrigine
Fp1-F7
F7-T3
T3-T5
T5-O1
Fp2-F8
F8-T4
T4-T6
T6-O2
Fp1-F3
F3-C3
C3-P3
P3-O1
Fp2-F4
F4-C4
C4-P4
P4-O2
Comment CLINICAL SZ EVENT Photic Start (20 Hz) Photic End (20 Hz)
Fp1-F7
F7-T3
T3-T5
T5-O1
Fp2-F8
F8-T4
T4-T6
T6-O2
Fp1-F3
F3-C3
C3-P3
P3-O1
Fp2-F4
F4-C4
C4-P4
P4-O2
Comment CLINICAL SZ EVENT Photic Start (20 Hz) Photic End (20 Hz)
Complex Partial Epilepsy
• Onset adolesence
through adulthood
• Most often of temporal
lobe origin
• Can be associated with
progressive hippocampal
scarring (mesial temporal
sclerosis) and cognitive
deficits
• AEDs: most any
Pyschogenic Nonepileptic
Seizures:PNES (older term
“Pseudoseizures” is discouraged)
Pyschogenic Non-Epileptic
Seizures (PNES)
• Considered a conversion disorder
• Typically, patients are not consciously manufacturing symptoms
• 70% Female preponderance
• Accounts for up to 30% of referrals for refractory epilepsy at epilepsy centers
• Most have received AEDs, some have been intubated for presumed status epilepticus
PNES
• High incidence PTSD, hx childhood sexual
abuse, other psychiatric comorbidities
• Video/EEG inpatient monitoring is highly
sensitive and specific for diagnosis
• Clinical diagnosis of seizures may be misleading
• Caution is required, since many patients exhibit
both epileptic seizures and PNES
• Psychiatric treatment is indicated but outcome is
variable.
Epilepsy Statistics
• Epilepsy and seizures affect almost 3 million
Americans of all ages, at an estimated annual
cost of $15.5 billion in direct and indirect costs.
• Approximately 200,000 new cases of seizures
and epilepsy occur each year.
• Ten percent of the American population will
experience a seizure in their lifetime.
• Three percent will develop epilepsy by age 75.
Source: Epilepsy Foundation of America http://www.epilepsyfoundation.org
Epilepsy prevalence in special
populations
• 10 percent of children with mental retardation
• 10 percent of children with cerebral palsy
• 50 percent of children with both disabilities
• 10 percent of Alzheimer patients
• 22 percent of stroke patients
• 8.7 percent of children of mothers with epilepsy
• 2.4 percent of children of fathers with epilepsy
• 33 percent of people who have had a single, unprovoked seizure
Risks of Epilepsy
• Injury from direct and indirect effects of seizures
• Sudden Unexpected Death in Epilepsy (“SUDEP”): varies with severity of epilepsy up to 10 deaths per 1000 patient-years
• Risks of treatment: reproductive and other
• Depression: Suicide risk 3 x control group in one study. FDA required warning placed on all AEDsEpilepsy and risk of suicide: a population-based case-control study. Lancet Neurol. 2007; 6(8):693-8.
• Socioeconomic marginalization due to decreased employability and socialization
• Long term cognitive declineCognitive Decline in Severe Intractable Epilepsy Epilepsia 2005 ; 46 (11) 1780 - 1787
• Bone demineralization with long term AED useEffect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002; 58:1348-1353
Epilepsy and Driving in Oregon
• New rules adopted state-wide June 2004 (ORS 807.710 and OAR 735-074)
• Requires physicians to report persons over 14 with “Severe and Uncontrollable Impairments” not limited to epilepsy –immunity from civil liability for doing so
• Seizure control for three months on therapy generally required for driving –duty to advise?
AED Long Term Side Effects
Bone Demineralization
• Older AEDs implicated, ?new AEDs also
• Multiple mechanisms, including:
• Decreased vitamin D levels
• Reduced calcium absorption
• Hyperparathyroidism
• Calcitonin deficiency
Bone Health Treatment
Recommendations
• Screen with DEXA after 5 years of AEDs, ?at
baseline in women before starting
• All patients should receive at least 1200 mg/day
of calcium
• All patients should receive supplemental vitamin
D, at least 400 IU/day – and check levels!
• If there is evidence of osteopenia, more
aggressive treatment (biphosphonates,
calcitonin)
Issues for Women with Epilepsy
Issues for Women with Epilepsy
• Estimated 500,000 women with epilepsy of
childbearing age in US
• 3-5 births per thousand in US are to
women with epilepsy
• Some AEDs have unique toxicities for
women
• Significant interactions between AEDs and
Oral Contraceptive Pills (OCPs)
Teratogenicity of AEDs
• All older AEDs are proven teratogens
• Valproic acid causes up to 10.7% risk of
Major Congenital Malformations (MCM);
persistently lower IQ in exposed children
• Polytherapy raises birth defect incidence
• Newer AEDs are category C; data is
accumulating in AED pregnancy registries
North American AED
Pregnancy Registry
• 7,242 women enrolled since 1997
• 1-888-233-2334
• www.aedpregnancyregistry.org
• Encourage all women on AEDs to call!
NA AED Pregnancy Registry:
% MCM on Monotherapy
0
2
4
6
8
10
12
None LTG CBZ VPA
%MCM
NA AED Pregnancy Registry:
% MCM on Polytherapy
0
2
4
6
8
10
12
None CBZ+LTG CBZ+VPA LTG+VPA
NEAD Study of IQ at age 3 for
children exposed in utero (p=0.009)
86
88
90
92
94
96
98
100
102
LTG PHT CBZ VPA
IQ at 3 yrs
Recommendations for Women
• All women of childbearing potential taking
AEDs should take 1mg/day folic acid
• Folic acid 4 mg/day if AED is valproic acid
• Avoid polypharmacy and VPA if possible
• Monitor pregnancy with ultrasonography at
11 and 16 weeks; check alpha fetoprotein
• Vitamin K 10 mg/day in last trimester to
prevent newborn hemorrhagic disease
Issues for Women with Epilepsy
Special Risks of Valproic Acid -
Polycystic Ovarian Syndrome:
• Affects 7% of all reproductive age women
• Excessive androgen sensitivity
• Signs include hirsutism, obesity, acne, alopecia
and anovulatory menstrual cycles
• Metabolic findings include hyperinsulinemia,
hyperlipidemia and glucose intolerance
• VPA therapy increases risk of developing
metabolic abnormalities similar to PCOS
Recommendations for Women –
AED Effect on Oral Contraceptives
No Effect on Low
Estrogen OCPs:
• Gabapentin
• Pregabalin
• Lamotrigine (but OCP will
lower levels)
• Levetiracetam
• Lacosamide
• Tiagabine
• Zonisamide
Estrogen <35 mcg May
be Ineffective for
Contraception:
• Barbiturates
• Carbamazepine
• Oxcarbazepine
• Phenytoin
• Topiramate
Diagnosis of Epilepsy
Diagnosis of Epilepsy
• Epileptic seizures or Non-epileptic spells?
• “Not everything that shakes is epilepsy”
• Careful history taking and direct
eyewitness reports of events can make a
diagnosis or guide further testing
• Try to get description (semiology) of event,
not a lay diagnosis (e.g. “petit mal”)
Diagnosis of Epilepsy:
Consider other causes of spells• Syncope (+/- convulsion): consider cardiac
dysrythmia or neurocardiogenic syncope
• Cerebrovascular disease – “Limb Shaking TIA”
• Migraine
• Movement disorders
• Hypoxia, hypoglycemia, toxins/drugs
• Psychiatric (“Pseudoseizure” is now discouraged
– prefer “Psychogenic Non-Epileptic Seizure”)
Diagnosis of Epilepsy - EEG
• Routine (interictal) EEG usually performed, sometimes helpful in guiding therapy
• Ambulatory EEG can improve diagnosis of questionable spells, but may be difficult to interpret
• Ictal Video/EEG is the gold standard – but inter-rater reliability is not perfect
Diagnostic Imaging of Epilepsy
• MRI (3 Tesla if available) is preferred over CT, except in acute trauma, and when contraindicated
• MRI can show subtle lesions such as mesial temporal sclerosis (arrow) not apparent on CT scans
Evaluation at the Epilepsy Center
• Invasive monitoring
(depth electrodes or
subdural grids) for
presurgical workup
Magnetoencephalography (MEG)
• Promising and increasingly used in epilepsy centers
• Measures the induced magnetic fields of the brain rather than directly measuring the electrical fields
• Can non-invasively record sources of epilepsy deep in the brain
• Still rather cumbersome
Diagnostic Imaging of Epilepsy -
SPECT and SISCOM
• SPECT (Single Photon
Emission Tomography)
shows areas of hypo- or
hyper-metabolism
• Ictal SPECT: IV push of
radiolabeled tracer during
seizure
• SPECT superimposed
on MRI yields „SISCOM‟
(Subtraction Ictal SPECT
Co-registered with MRI)
Pharmacologic
Treatment of Epilepsy
Antiepileptic Drug (AED)
Selection Guidelines
• Start with a safe AED appropriate for the specific
epilepsy syndrome, as monotherapy if possible
• “Start low, go slow” if possible
• Individualize AED to patient characteristics (e.g
obese, female, elderly)
• Consider potential benefits for comorbid
conditions (e.g. migraine, mood disorder, pain)
• Consider patient compliance (prefer QD or BID
dosing) and drug interactions
AED Selection GuidelinesPrimary Generalized
Epilepsies:
• Valproic Acid
• Felbamate
• Lamotrigine
• Levetiracetam
• Topiramate
• Phenobarbital
• Zonisamide (may worsen
myoclonic epilepsies)
Partial or Secondarily
Generalized Epilepsy:
Any AED may be effective
except ethosuximide
(effective only for
absence)
*Note: carbamazepine may
worsen absence epilepsy
Benefits of AEDs for Cormorbidities
• Bipolar Disorder: VPA, CBZ, OXC, LTG
• Migraine: TPM, VPA
• Painful Neuropathy: PGB, CBZ, TPM
• Trigeminal Neuralgia: CBZ, PGB, VPA
Cognitive AED Side Effects
• All AEDs can impair cognition
• Some correlation between AED efficacy and cognition ( „strong‟ AEDs worse)
• Lamotrigine and levetiracetam in general to cause less impairment.
• Many patients have idiosyncratic cognitive AED side effects
• Some AEDs more associated with psychiatric SEs (levetiracetam, felbamate, tiagabine)
• Suicide risk warning placed on all AEDs
AED by Mechanism of Excretion: Primarily Hepatic vs. Primarily Renal
• Phenobarbital
• Phenytoin
• Carbamazepine
• Valproic Acid
• Felbamate
• Lamotrigine
• (Gapapentin)
• Pregabalin
• Levetiracetam
• Lacosamide
AED selection by
Mechanism of Action
• Controversial even among epileptologists……
AED Selection – pharmacologic
considerations
• Hepatic Enzyme inducers vs. non-inducers
• Plasma Protein binding
• Half-life
• Drug-drug interactions: note particularly
valproic acid which can markedly inhibit
lamotrigine metabolism
Pharmacogenomics
• Promising approach to choosing medication best suited to an individual
• Currently in technological infancy
• Practical application reflected in new black box labeling for carbamazepine
• Increased incidence of Stevens Johnson Syndrome in Asians with HLA-B*1502
• Testing recommended before placing individual of Asian descent on CBZ
Phenytoin Side Effects:
Expected vs. Idiosyncratic
• Ataxia, dizziness
• Gingival hyperplasia
• Hirsuitism, coarsening
of facial features
• Cerebellar
Degeneration,
peripheral neuropathy
• Rash, including
Stevens Johnson
• Hepatitis
• Other hypersensitivity
reactions
• Lupus like syndrome
• Purple Glove
Syndrome
Carbamazepine Side Effects:
Expected vs. Idiosyncratic
• Ataxia
• Diplopia
• Dizziness
• Photosensitivity
• Mild neutropenia
• Hyponatremia
• Rash, including
Stevens Johnson
• Hepatitis
• Severe Neutropenia
Valproic Acid Side Effects:
Expected vs Idiosyncratic
• Sedation
• Tremor
• Weight gain
• Change in hair growth
• Mild
thrombocytopenia
• Fulminant hepatic
failure (mostly infants)
• Pancreatitis
• Valproate
encephalopathy
Felbamate Side Effects:
Expected vs Idiosyncratic
• Sleeplessness
• Agitation
• Headache
• Loss of appetite/
• Weight loss
• Aplastic Anemia (risk
1 in 3000 – 5000)
• Fulminant Hepatic
Failure
• Psychosis
Lamotrigine Side Effects:
Expected vs. Idiosyncratic
• Sedation
• Dizziness
• Diplopia
• Headache (may
worsen pre-existing
migraines)
• Rash, including
Stevens Johnson
Syndrome
Topiramate Side Effects:
Expected vs. Idiosyncratic
• Extremity paresthesias
• Altered taste of carbonated bevs
• Mild cognitive side effects, “spaciness”
• Weight loss
• Mild metabolic acidosis, increased risk of nephrolithiasis
• Acute angle closure glaucoma
• Severe cognitive side effects “zombie”
• Severe metabolic acidosis
Pregabalin Side Effects:
Expected vs. Idiosyncratic
• Sedation
• Dizziness
• Weight Gain
• Pedal edema
• Angioedema
Levetiracetam Side Effects:
Expected vs. Idiosyncratic
• Drowsiness
• Dizziness
• Mild Irritability
• Severe Mood disorder
• Psychosis
Oxcarbazepine Side Effects:
Expected vs. Idiosyncratic
• Headache
• Dizziness
• Nausea
• Diplopia
• Hyponatremia
• Rash, including
Stevens Johnson
Syndrome
• Severe Hyponatremia
Lacosamide Side Effects:
Expected vs. Idiosyncratic
• Dizziness
• Diplopia
• Drowsiness
• Ataxia
• Prolonged P-R
interval
• Hepatitis
Dietary Therapy for Epilepsy
• Ketogenic diet has proven track record in
children with intractable epilepsy, safety
questions remain
• Now efficacy has been demonstrated in
adults
• Compliance is problematic
Status Epilepticus
• Defined as seizure activity, either
continuous or intermittent, lasting greater
than 30 minutes without return to baseline
level of consciousness
• Constitutes a medical emergency
• Can result in neuronal cell death, even if
blood pressure and oxygenation is
maintained
Status Epilepticus Subtypes
• Simple Partial
• Complex Partial
• Generalized Convulsive
• Generalized Non-convulsive
• For a patient presenting with “lights on,
nobody home”, EEG required for diagnosis
of non-convulsive status epilepticus
Status Epilepticus: Causes
• Approx 1/3 due to exacerbation of pre-
existing idiopathic epilepsy, often with
medication non compliance
• 1/3 new presentation of epilepsy without
other identified cause
• 1/3 due to other: structural,
toxic/metabolic, infectious causes
Status Epilepticus: Initial evaluation
• Rule out hypoglycemia and electrolyte
imbalance
• Rule out poisoning or overdose
(stimulants, TCAs, INH)
• Rule out drug or alcohol withdrawal
• Rule out CNS mass or infection (CT scan
and CSF examination)
Status Epilepticus:
Standard Treatment
• ABCs and maintain normothermia
• Treat any identified underlying cause
• LORAZEPAM 4mg IV over 2 minutes,
repeat if needed in 15 mins (Adults) OR
DIAZEPAM 5-10 mg IV load (Adults)
• PHENYTOIN (infuse at<50mg/min) OR
FOSPHENYTOIN (up to 150mg/min,
preferred) loading dose 15-20mg/Kg
Refractory Status Epilepticus: Old
School Approach, still standard
• Standard third line agent: PHENOBARBITAL 15-20mg/Kg IV – likely to cause respiratory depression given after benzodiazepines
• Rapid sequence intubation, EEG monitoring, ICU management as needed
• Standard IV continuous therapy: PENTOBARBITAL 12mg/kg IV load then 5mg/Kg/hr IV, follow EEG monitoring
Status Epilepticus: current trends,
(off label use, no RCT data)
• Second line use of any available IV formulated AED – VALPROIC ACID, LEVETIRACETAM, LACOSAMIDE
• Third line use of IV MIDAZOLAM 0.2mg/Kg IV load, then 0.1–0.4 mg/Kg/min drip titrated to clinical effect or EEG
• Third line use of IV PROPOFOL 2mg/Kg IV load, then 0.1 – 0.2 mg/Kg/min IV drip (caution re:acidosis with prolonged use)
Surgical Treatment
of Epilepsy
Surgical Treatment of Epilepsy
• Variety of procedures available, two devices currently awaiting approval
• Requires extensive inpatient workup
• Treatment of choice for many patients with pharmacoresistant epilepsy
• Offers chance of epilepsy remission for some refractory patients
Brain Resection Surgery
Successful Outcome Involves many steps
• Accurate diagnosis
• Appropriate patient selection
• Pre-op localization of seizure focus
• Intra-operative seizure recording and functional mapping
The Future is Here!
• Clinical trial completed of
Responsive Neuro
Stimulation (RNS)
• “Brain Defibrillator”
• Electrodes implanted into
seizure focus
• Computer senses and
delivers countershock to
stop seizure
• Currently awaiting FDA
approval
Anterior Thalamic DBS for Epilepsy
• Uses same technology as for Parkinsons
• Awaiting FDA approval
Summary
• The 20th century saw an explosion of new
antiepileptic drugs
• The 21st century will see an explosion of
high-tech implantable devices and drugs
• Best patient care still begins with a
thorough history
• Careful consideration and explanation of
risks and benefits is essential
Questions?